In a study of 114 epidemiologically linked Zambian transmission pairs, we
evaluated the impact of human leukocyte antigen class I (HLA-I)-associated amino
acid polymorphisms, presumed to reflect cytotoxic T lymphocyte (CTL) escape in
Gag and Nef of the virus transmitted from the chronically infected donor, on the
plasma viral load (VL) in matched recipients 6 mo after infection. CTL escape
mutations in Gag and Nef were seen in the donors, which were subsequently
transmitted to recipients, largely unchanged soon after infection. We observed a
significant correlation between the number of Gag escape mutations targeted by
specific HLA-B allele-restricted CTLs and reduced VLs in the recipients. This
negative correlation was most evident in newly infected individuals, whose HLA
alleles were unable to effectively target Gag and select for CTL escape mutations
in this gene. Nef mutations in the donor had no impact on VL in the recipient.
Thus, broad Gag-specific CTL responses capable of driving virus escape in the
donor may be of clinical benefit to both the donor and recipient. In addition to
their direct implications for HIV-1 vaccine design, these data suggest that
CTL-induced viral polymorphisms and their associated in vivo viral fitness costs
could have a significant impact on HIV-1 pathogenesis.